The insulin-like growth factor receptor (IGF-1R) is one of 58 trans-membrane tyrosine kinase receptors present in humans [Review: Structure and function of the Type 1 insulin-like growth factor receptor. T. E. Adams et al. Cell. Mol. Life Sci. 57 (2000) 1050-1093]. Genetic evidence and studies on cells lacking the IGF-1 receptor have demonstrated that it is required for optimal growth, but not an absolute condition for growth [Baserga et al. Biochim. Biophys. Acta 1332(1997) 105-126]. An expression of the IGF-1 receptor protects cells from apoptosis and seems to be a requirement for the establishment and maintenance of the transformed phenotype both in vitro and in vivo [R. Baserga et al. Biochim. Biophys. Acta 1332 (1997) 105-126]. Several in vitro and in vivo studies have demonstrated that inhibition of the expression or function of the IGF-1 receptor reverses the transformed phenotype and inhibits tumor cell growth. The techniques used in these studies include neutralizing antibodies [Kalebic et al. Cancer Res. 54(1994) 5531-5534], antisense oligonucleotides [Resnicoff et al. Cancer Res. 54(1994) 2218-2222], dominant negative receptors [D'Ambrosio et al. Cancer Res. 56(1996) 4013-4020], triple-helix forming oligonucleotides [Rinninsland et al. Proc.Natl. Acad. Sci. 94(1997) 5854-5859], antisense mRNA [Nakamura et al. Cancer Res. 60(2000) 760-765] and RNA interference using a double stranded RNA (V. M. Macaulay et al. WO-A-03/100059).
The use of antisense oligonucleotides to inhibit the IGF-1 receptor expression in keratinocytes has been shown to reverse the epidermal hyper proliferation in psoriasis lesions [C. J. Wraight et al. Nat. Biotechnol. 18(2000) 521-526].
Down-regulation of the IGF-1 receptor would possibly also have beneficial effect with respect to diseases such as diabetic retinopathy [L. K. Shawver et al. DDT 2(1997) 50-631] as well as atherosclerosis and restenosis [A. Bayes-Genis et al. Circ. Res. 86(2000) 125-130].
The IGF-1 receptor system is regarded as an attractive target in the prevention and/or treatment of diseases that are dependant on an expression or over-expression of the IGF-1 receptor for their proliferation [L. Long et al. Cancer Research 55(1995) 1006-1009, R. Baserga TIBTECH 14(1996) 150-152; R. Baserga et al. Endocrine 7 (August 1997) 99-102; V. M. Macaulay et al. Annals of Oncogene 20 (2001) 4029-4040].
A series of substances, named tyrphostins, have been claimed to down-regulate or inhibit the expression of the IGF-1 receptor [M. Parrizas et al. Endocrinology 138 (1997) 1427-1433; G. Blum et al. Biochemistry 39(2000) 15705-15712; G. Blum et al. J. Biol. Chem. 278 (2003) 40442-404541]. The drawback with the tyrphostins are their low activity in cell systems and that they cross-react with the insulin receptor.
It has been demonstrated [L. Kanter-Lewensohn et al. Mol. Cell. Endocrinology 165 (2000) 131-137] that tamoxifen, at high concentration, has the ability to down-regulate or inhibit the tyrosine phosphorylation of the IGF-1R β-subunit, thereby blocking downstream signalling.
In U.S. Pat. No. 6,337,338 b1, a number of heteroaryl-aryl urea substances-are described as antagonists of the IGF-1 receptor. In cell growth inhibition studies on MCF-7 and MCF-10 cell lines the substances showed low activities.
In the patent publication WO 02/102804 A1 it is demonstrated that podophyllotoxin, deoxypodophyllotoxin, picropodophyllin and deoxypicropodophyllin are selective and efficient inhibitors of the IGF-1 receptor. Deoxypicropodophyllin has previously [A. Akahori et al. Chem. Pharm. Bull. 20(1972) 1150-1155] been shown to be superior to deoxypodophyllotoxin in retarding the death of mice inoculated with lymphatic leukemia L1210. No mechanism of action, however, was proposed.
In the patent publication WO 02/102805 A1 it is shown that also acetylpodophyllotoxin, epipodophyllotoxin, podophyllotoxone and 4′-demethylpodophyllotoxin are potent inhibitors of the IGF-1R phosphorylation.
In the patent publication WO 03/048133 A1 a number of pyrimidine derivatives are described as modulators of the IGF-1 receptor.
The present invention aims to provide compounds with improved IGF-1R down-regulating activity.